This application for renewal of R01 DK 052291-05 proposes to further study the role of vagal afferents in the perpetuation of binge-eating and vomiting. We previously proposed that the pathophysiology of bulimia nervosa involves dysregulation of the afferent vagus nerve. During the last funding period, this hypothesis was tested using two main strategies: (1) the use of somatic pain detection as a physiological marker of vagal afferent activity; and (2) the use of ondansetron (a 5 HT3 antagonist known to reduce vagal neurotransmission) as a pharmacological challenge test of vagal modulation of both the bulimic behaviors and on elevated pain detection thresholds. The principle findings from these studies are: 1) pain detection thresholds rise dynamically across the interval between bulimic binge/vomit episodes, apparently reaching their zenith as the next bulimic episode is approached and dropping to their nadir in close temporal association with having recently engaged in a bulimic episode; and (3) ondansetron treatment was associated with a significant moderation in both the cyclic fluctuations in pain detection thresholds and the primary disorder symptom of binge/vomit episodes per week in a group of patients with severe and chronic bulimia nervosa under randomized, placebo controlled, double-blind condition. Collectively, the above summarized physiological and clinical data have led to the refined hypothesis that the pathophysiology of bulimia nervosa involves a cyclic hyperactivity in vagal afferent nerves. This overall hypothesis will be tested through an interactive combination of clinical pharmacology and psychophysiological approaches. Specific Aim I will investigate the association between disorder severity as indicated by binge/vomit frequencies and dynamic changes in pain detection thresholds. The approach of this Aim is based on the idea that if dynamic increases in vagal activity drive bulimic episodes, then the rate of cyclic changes in vagal activity should be a significant statistical predictor of the frequency of bulimic behaviors. Specific Aim II will investigate the effect of psychotherapeutic intervention on physiological indices of vagal activity, namely thresholds for pain detection and induction of satiety. The approach of the Aim is based on the idea that if vagal hyperactivity represents the critical factor involved in symptom production, then any therapeutic method resulting in a decrease in symptoms would be predicted to be accompanied by a demonstrable correction in vagal function. In addition to generating important basic science information on vagus nerve function in bulimia nervosa, these studies will also provide insight into the utility of ondansetron in the clinical treatment of this debilitating disorder.